(Adapted from the applicant's abstract): The primary hypotheses of the proposed project is that administration of Donepezil to young adults with Down syndrome (DS) will improve adaptive functioning and expressive language as measured by a change from baseline to endpoint at 24 weeks of therapy. DS is the most common genetic cause of mental retardation worldwide. Cognitive and functional deficits, of variable degree, are seen in all subjects with DS and currently there is no approved treatment for these domains. An impaired cholinergic system, which persists throughout the lifespan, has been detected early in life in individuals with DS. This cholinergic deficit is believed to underlie many of the cognitive and functional impairments in DS. A therapy that increases the bioavailability of acetylcholine could produce improvements in cognition and consequently, adaptation in DS. Alzheimer's disease (AD) is a model for this effect. Donepezil Hydrochloride, an FDA-approved second generation cholinesterase inhibitor, is currently the most widely-used medication for the pharmacotherapy of cognitive and functional deficits in AD. A previous open label study of DS adults found Donepezil to be well tolerated with improvement in expressive language and adaptive domains. Rationale for its use in young DS individuals is to enhance availability of acetylcholine because of its key role in learning and not to treat symptoms of AD in DS. The proposed study is a single Center, randomized 24-week double-blind, placebo-controlled study with a subsequent 24-week open treatment and six-week washout phases. Sixty individuals with DS will participate, and half will receive drug during the first 24 weeks. The primary endpoints are the adaptive behavior composite score of the Vineland Adaptive Behavior Scales (VABS) and expressive language subtests of the Clinical Evaluation of Language Fundamentals (CELF-3) comparing the treated group to the control group after the 24 weeks of blinded treatment. A number of secondary aims will investigate effects of treatment of specific components of cognition, i.e., memory and mood. Safety and tolerability will also be evaluated. As DS individuals are now living longer, improving their quality of life and maximizing their developmental potential are of paramount importance.